MBoC  |  PERSPECTIVE

Why should cell biologists study microbial

pathogens?
Matthew D. Welch
Department of Molecular & Cell Biology, University of California, Berkeley, Berkeley, CA 94720

ABSTRACT  One quarter of all deaths worldwide each year result from infectious diseases Monitoring Editor
caused by microbial pathogens. Pathogens infect and cause disease by producing virulence Doug Kellogg
University of California,
factors that target host cell molecules. Studying how virulence factors target host cells has
Santa Cruz
revealed fundamental principles of cell biology. These include important advances in our un-
derstanding of the cytoskeleton, organelles and membrane-trafficking intermediates, signal Received: Jul 15, 2015
transduction pathways, cell cycle regulators, the organelle/protein recycling machinery, and Revised: Aug 12, 2015
cell-death pathways. Such studies have also revealed cellular pathways crucial for the immune Accepted: Aug 14, 2015
response. Discoveries from basic research on the cell biology of pathogenesis are actively
being translated into the development of host-targeted therapies to treat infectious diseas-
es. Thus there are many reasons for cell biologists to incorporate the study of microbial
pathogens into their research programs.

INTRODUCTION
Infectious diseases cause approximately one quarter of all deaths
worldwide each year (Fauci and Morens, 2012). These include the
“big three”—HIV/AIDS, tuberculosis, and malaria—which account
for 10% of all deaths. They also include emerging diseases such as
Ebola, Middle East Respiratory Syndrome, and methicillin-resistant
Staphylococcus aureus. Infections are caused by microbial patho-
gens from different domains of the tree of life—viruses, bacteria, or
eukaryotes. All share the ability to colonize their hosts and cause
pathology through their interactions with host cells.
To influence host cells, each pathogen produces a distinct set of
virulence factors that target specific host cell structures, pathways,
and molecules. The function of virulence factors differs depending
on where the pathogen establishes residence (Figure 1). Extracellu-
lar pathogens reside around or in contact with host cells but resist
internalization into cells. They produce virulence factors that inhibit
phagocytosis and otherwise disable elements of the immune re-
sponse. Intracellular pathogens instead encourage their internaliza-
tion into host cells, grow within a preferred cellular compartment or
DOI:10.1091/mbc.E15-03-0144
Address correspondence to: Matthew D. Welch (welch@berkeley.edu).
Abbreviations used: A-MuLV, Abelson murine leukemia virus; BCG, bacillus
Calmette-Guerin; RSV, Rous sarcoma virus; SCV, Salmonella-containing vacuole.
© 2015 Welch. This article is distributed by The American Society for Cell Biology
under license from the author(s). Two months after publication it is available to
the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Cre-
ative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).
“ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of
the Cell®” are registered trademarks of The American Society for Cell Biology.
organelle, and then exit the cell to disseminate the infection. They
produce virulence factors that promote phagocytosis, enable move-
ment to their preferred compartment, manipulate membrane traf-
ficking and autophagy to resist killing and permit growth and repli-
cation, and exit the cell to promote spread.
The cellular and molecular targets of pathogen virulence factors
are the same systems studied by most cell biologists. They include:
the cytoskeleton, organelles and membrane-trafficking intermedi-
ates, signal transduction pathways, cell cycle regulators, the organ-
elle and protein recycling machinery, and cell-death pathways
(Table 1). Studying the mechanisms by which virulence factors target
host cells has two important impacts. First, such studies reveal cru-
cial mechanisms of infection. Second, these studies aid in the eluci-
dation of fundamental cellular mechanisms—for example, tyrosine
kinase signaling or actin-based motility, to name a very few.
The study of pathogen interactions with host cells also has practi-
cal impacts on fighting infectious diseases. One is advancing our
understanding of immunity. Immune cells are often the targets of
pathogen virulence factors, and understanding the interactions of
pathogens with immune cells enhances the development of effec-
tive immune-based therapies for infections. Another is identifying
cellular molecules crucial for infection, which are then exploited as
targets of drugs to treat infectious diseases.
In this Perspective, I provide concrete answers to the basic ques-
tion posed in the title: Why should cell biologists study microbial
pathogens? Along the way, I explore three smaller questions: What
have we learned about basic cell biology from studying pathogens
and their virulence factors? What has studying the cell biology of
host–pathogen interactions taught us about immunity? How has

Volume 26  December 1, 2015 4295 

 extracellular pathogens intracellular pathogens inhibit phagocytosis by producing virulence
factors that disable Rho, Rac, and/or Cdc42,
Clostridium species, others Trypanosoma cruzi
highlighting the generality of this patho-
genic strategy (Lemichez and Aktories,
inhibit promote 2013). Bacterial toxins continue to be im-
phagocytosis phagocytosis
portant tools for revealing the functions of
Rho GTPases in cells.
Rho GTPases lysosome The study of pathogens that mobilize ac-
disable Ca 2+
actin manipulate tin for movement has also led to the discov-
secretion
autophagy ery of fundamental mechanisms of cytoskel-
septins Salmonella, Legionella etal dynamics and regulation. Such
nucleus p62, NDP52 pathogens include the bacteria Listeria
SNAREs
monocytogenes, Shigella flexneri, and
DNA tumor Listeria, Shigella alter Escherichia coli, which cause food-borne ill-
viruses Rab, Arf trafficking nesses, as well as vaccinia virus, which is the
smallpox vaccine strain. These microbes un-
alter dergo actin-based motility either within or
cell cycle caspase-1 on the surface of cells, which enables cell-
pRb, Cdks, inflammasomes to-cell spread during infection (Welch and
cyclins Arp2/3, actin p53, Bcl-2 Way, 2013). Through biochemical reconsti-
promote movement influence cell death tution of L. monocytogenes and/or S. flex-
neri motility, the host Arp2/3 complex and
its activators (the WASP family proteins)
FIGURE 1:  Pathogen virulence factors influence cellular pathways and structures. Extracellular were revealed as key actin-nucleating fac-
pathogens produce virulence factors that act at a distance or on contact with a host cell. These tors for bacterial pathogens and host cells
virulence factors inhibit cellular processes (indicated by red) including phagocytosis and (Welch et al., 1997, 1998), and a minimal set
secretion. In contrast, intracellular pathogens produce virulence factors that promote intimate of proteins that is sufficient to drive actin-
interactions with host cells. These activate cellular processes (indicated by green), including
based motility was defined (Loisel et al.,
phagocytosis, intracellular movement to a preferred compartment or organelle, and cell-to-cell
1999). Moreover, the study of enteropatho-
spread. Virulence factors can also either activate or inactivate cellular processes (indicated by
orange) to prevent microbial killing and enable growth and replication. These pathways include genic/enterohemorrhagic E. coli and vac-
those involved in membrane trafficking, autophagy, cell death, and cell cycle regulation. cinia virus, which induce actin assembly
from outside the cell through the plasma
membrane, revealed important roles for ty-
identifying cellular targets of pathogens led to the development of rosine kinase signaling and protein clustering in regulating actin as-
therapeutic agents to treat infection? sembly (Frischknecht et al., 1999; Campellone et al., 2008).
Studying pathogens has also led to fundamental advances in the
WHAT HAVE WE LEARNED ABOUT BASIC CELL BIOLOGY field of membrane trafficking. A classic example involves the extra-
FROM STUDYING PATHOGENS AND THEIR VIRULENCE cellular bacterial pathogens C. botulinum, mentioned above, as well
FACTORS? as Clostridium tetani, which causes the paralytic disease tetanus. In
The study of how pathogens and their virulence factors impact host addition to the C3 exoenzyme, C. botulinum produces botulinum
cells has been fertile ground for uncovering basic cell biological toxins A–G (type A is familiarly known as Botox), and C. tetani se-
principles and mechanisms. Such discoveries have enhanced our cretes tetanus toxin. These toxins specifically cleave SNARE protein
understanding of the many structures, pathways, and molecules components of the vesicle fusion machinery, including VAMP, SNAP-
that are commonly exploited by pathogens during infection. 25, and syntaxin (Link et al., 1992; Schiavo et al., 1992; Blasi et al.,
One area of cell biology in which the study of pathogens has 1993a,b). Microinjection of nerve cells with these toxins showed that
enabled fundamental advances is the cytoskeletal field. Extracellular SNARE molecules are critical for neurotransmitter release via vesicle
bacterial pathogens often target actin or its regulators by secreting fusion with the plasma membrane (Schiavo et al., 1992; Blasi et al.,
toxins that translocate across cellular membranes to inhibit phago- 1993b). Preventing neurotransmitter release results in the paralysis
cytosis by immune cells (Lemichez and Aktories, 2013). An example caused by botulinum and tetanus toxins. In a contemporary study, it
is Clostridium botulinum, which causes the paralytic illness botulism. was revealed that SNARE proteins form a complex that is sufficient
C. botulinum produces several secreted toxins, including C3 toxin, to mediate vesicle docking and fusion (Söllner et al., 1993). Thus
which enters host cells and ADP-ribosylates and inactivates the Rho bacterial toxins were used in discovering fundamental mechanisms
family GTPase Rho (paralysis is caused by a separate toxin, as dis- of membrane fusion and vesicular transport.
cussed below; Narumiya et al., 1988; Aktories et al., 1989). By exam- Advances in our understanding of how membrane-trafficking
ining the effect of microinjecting C3 toxin into cells, Alan Hall and pathways contribute to repairing plasma membrane wounds
coworkers discovered that Rho signals to promote the formation of (Sonnemann and Bement, 2011) have also come from the study of
focal adhesions and stress fibers (Chardin et al., 1989; Paterson intracellular pathogens. A classic example is Trypanosoma cruzi, a
et al., 1990; Ridley and Hall, 1992). Sadly, Alan passed away earlier eukaryotic parasite and the causative agent of Chagas disease,
this year in the prime of his career. Similar studies showed that Rho which in its chronic form can cause cardiovascular and intestinal ill-
family proteins are also required for phagocytosis (Hall, 2012). Many ness. As the T. cruzi parasite contacts the plasma membrane of a
bacteria, such as Clostridium difficile, the leading cause of hospital- host cell before invasion, intracellular Ca2+ is elevated, and cellular
acquired diarrhea, or Yersinia pestis, the causative agent of plague, lysosomes are recruited to the point of contact between the parasite

4296 | M. D. Welch Molecular Biology of the Cell

 Pathway/structure Pathogenic process Pathogens Host targets References
Cytoskeleton Inhibit phagocytosis Many extracellular pathogens, e.g., Rho proteins, actin Lemichez and
Clostridium spp., Yersinia spp. Aktories, 2013
Phagocytosis Most intracellular pathogens Rho proteins, signaling Pizarro-Cerdá and
proteins, phagocytic Cossart, 2006
proteins, actin
Movement, spread Many pathogens, e.g., L. monocy- Arp2/3 complex, Welch and Way,
togenes, S. flexneri, E. coli, vaccinia signaling proteins, 2013
virus actin
Membrane Growth/replication Many extracellular pathogens, e.g., C. SNARE proteins, Rab Asrat et al., 2014
trafficking botulinum, C. tetani; many intracel- proteins, Arf proteins
lular pathogens, e.g., T. cruzi, L. pneu-
mophila
Cell cycle Growth/replication Many viruses, e.g., adenovirus, human pRb, cyclins, Cdks Bagga and
papilloma virus, SV40 Bouchard, 2014
Signal transduction Growth/replication Many pathogens, e.g., vaccinia virus, Tyrosine kinases, other Martin, 2004
RSV, A-MuLV kinases, GTPases, lipid
modifiers
Autophagy Growth/replication Many intracellular pathogens, e.g., S. NDP52, p62, optineurin Mostowy, 2014;
Typhimurium, L. monocytogenes, S. Sorbara and
flexneri, M. tuberculosis Girardin, 2015
Cell death Growth/replication Many pathogens, e.g., S. Caspase-1, inflamma- Guo et al., 2015
Typhimurium, P. falciparum somes, p53, Bcl-2
This table is meant to provide important and interesting examples without being comprehensive.

TABLE 1:  Summary of cellular pathways targeted by pathogens.

and host cell. Surprisingly, lysosomes participate in exocytosis at the
invasion site, which facilitates invasion (Tardieux et al., 1992, 1994).
It was later revealed that the Ca2+-dependent fusion of lysosomes
(Reddy et al., 2001) and other organelles (Shen et al., 2005) plays a
key role in repairing plasma membrane wounds in uninfected cells.
Along with work on T. cruzi, studying how intracellular bacterial
pathogens such as Legionella pneumophila, the causative agent of
Legionnaire’s disease, manipulate membrane-trafficking pathways is
advancing our understanding of these pathways in uninfected cells
(Asrat et al., 2014).
Cell cycle regulatory mechanisms have also been exposed
through the investigation of virus interactions with host cells (Bagga
and Bouchard, 2014). Classic examples involve the study of DNA
tumor viruses, which include adenovirus, human papilloma virus, and
SV40. These viruses rely on the host DNA replication machinery, and
thus they induce cell cycle progression into S phase to favor viral
DNA replication. A key discovery was that these viruses encode pro-
teins, such as E1A from adenovirus, that bind to the tumor-suppres-
sor protein pRb and related proteins (Whyte et al., 1988). The role of
pRb as a negative regulator of cell cycle progression was subse-
quently revealed when it was found that E1A binding to pRb com-
petes with and releases the bound transcription factor E2F, which
turn activates the expression of cell cycle regulatory genes that pro-
mote entry into S phase (Bagchi et al., 1991; Bandara and La
Thangue, 1991; Chellappan et al., 1991; Raychaudhuri et al., 1991).
Other viruses target different cell cycle regulators, including Cdks
and cyclins (Bagga and Bouchard, 2014), and studying how viruses
manipulate host cells will continue to reveal cell cycle regulatory
mechanisms.
Finally, our understanding of signal transduction pathways and
their contribution to diseases like cancer has also been heavily
influenced by the study of viruses (Martin, 2004). Famous examples
are the Rous sarcoma virus (RSV), which causes sarcomas in chick-
ens, and Abelson murine leukemia virus (A-MuLV), which causes
lymphosarcomas in mice. The capacity of RSV to transform normal
cells into tumor cells was found to be associated with the viral src
gene and its product v-Src (Brugge and Erikson, 1977; Weiss et al.,
1977). The v-Src protein and the v-Abl protein from A-MuLV were
subsequently shown to be tyrosine kinases (Hunter and Sefton,
1980; Witte et al., 1980), the first discovery of this protein class. Cel-
lular homologues of these proteins, c-Src and c-Abl, were soon
identified (Stehelin et al., 1976; Shalloway et al., 1981; Heisterkamp
et al., 1982), demonstrating that viral oncogenes are derived from
cellular counterparts. It was also soon recognized that the human
ABL1 gene, which encodes c-Abl, participates in the Philadelphia
chromosomal translocation, which is commonly associated with leu-
kemias (de Klein et al., 1982). Thus viruses were key to demonstrat-
ing the importance of tyrosine kinases in signaling in normal and
cancer cells and the roles of oncogenes in cancer. Future studies of
pathogens will continue to reveal ways in which diverse signaling
pathways and proteins influence normal cell physiology and
disease.
WHAT CAN STUDYING THE CELL BIOLOGY OF
HOST–PATHOGEN INTERACTIONS TEACH US ABOUT
IMMUNITY?
Cells of the immune system are often targeted by pathogens to
avoid or subvert immune defenses. Certain facets of the interaction
between pathogens and immune cells lie at the interface between
the fields of immunology and cell biology. The study of such areas is
of increasing importance in understanding general mechanisms of
pathogenesis, and may prove particularly relevant in harnessing the

Volume 26  December 1, 2015 Cell biology of pathogenesis | 4297 

immune system to fight infection. In this section, I highlight emerging
areas of intersection between basic cellular pathways and the innate
immune response to pathogens. In the subsequent section, I dis-
cuss how studying these areas impacts the development of thera-
peutics to treat infectious diseases.
Autophagy has emerged as a process that is of central inter-
est in the fields of cell biology and immunology, and research in
both disciplines has synergized to reveal key ways in which au-
tophagy impacts basic cell function and disease. Studies by cell
biologists have uncovered the importance of autophagy in main-
taining homeostasis during normal, stressful, or disease condi-
tions, and have identified important molecular players in this
pathway (Boya et al., 2013). Immunologists have discovered that
autophagy of pathogens (also called xenophagy) is an important
arm of the innate immune response that promotes intracellular
pathogen sequestration in autophagosomes and their degrada-
tion in lysosomes (Huang and Brumell, 2014; Sorbara and
Girardin, 2015).
An example of how studying pathogens has advanced our under-
standing of autophagy mechanisms involves the response to infec-
tion by the intracellular pathogen Salmonella enterica serovar Ty-
phimurium (S. Typhimurium), a common cause of diarrheal illness. S.
Typhimurium normally resides within an endosome-like compartment
called the Salmonella-containing vacuole (SCV). However, observa-
tion of the bacteria that occasionally damage the SCV and escape
into the cytosol enabled the discovery of previously unknown mecha-
nisms by which pathogens are targeted to autophagy. These include
marking bacteria in the cytosol with ubiquitin (Thurston et al., 2009)
and marking those in damaged SCVs with the lectin galectin-8, which
recognizes glycans on damaged vacuoles (Thurston et al., 2012).
Both galectin-8 and ubiquitin are then recognized by adapter pro-
teins (including NDP52, p62, and optineurin), which recruit LC3 and
initiate autophagosome formation (Thurston et al., 2009, 2012;
Zheng et al., 2009; Wild et al., 2011). In addition to their roles in infec-
tion, these same pathways may be involved in targeting damaged
organelles in uninfected cells (Huang and Brumell, 2014; Sorbara and
Girardin, 2015) and in removing protein aggregates, for example,
those associated with neurodegenerative diseases (Rubinsztein et al.,
2015).
A second example highlights how the study of pathogens can
reveal new pathways that influence autophagy, such as an emerging
link between cytoskeletal elements and the autophagy machinery
(Mostowy, 2014). In the case of L. monocytogenes, the ability of the
bacterial ActA protein to recruit actin-polymerizing factors masks
the bacteria from ubiquitination and the initiation of autophago-
some formation (Yoshikawa et al., 2009). This suggests a potential
role for actin in autophagy inhibition. In contrast, for S. flexneri, re-
cruitment of actin promotes the subsequent recruitment of septin
proteins, which cage the bacteria and are crucial for autophagy
(Mostowy et al., 2010, 2011). Thus, in the case of S. flexneri, actin
and septins play a stimulatory role in autophagy. Deciphering the
roles of cytoskeletal elements in autophagy regulation and the in-
nate immune response should be an active area of future
investigation.
Beyond autophagy, the study of pathogens has revealed previ-
ously unappreciated pathways for regulating programmed cell
death that are integral to innate immunity and inflammation. One
such pathway was discovered by studying cell death induced by S.
Typhimurium. It was noted that S. Typhimurium infection induced
cell death in macrophages that was dependent on caspase-1 (Hersh
et al., 1999). Moreover, the characteristics of death were distinct
from apoptosis in key respects, including diffuse rather than com-
4298 | M. D. Welch Molecular Biology of the Cell
pacted DNA fragmentation, and loss rather than maintenance of
plasma membrane integrity (Brennan and Cookson, 2000). This
mechanism of cell death was subsequently called pyroptosis, which
is a proinflammatory cell death, to distinguish it from apoptosis,
which is anti-inflammatory. Subsequent studies showed that cas-
pase-1 activation involves a multiprotein complex called an inflam-
masome (Martinon et al., 2002), of which there are multiple variet-
ies with different functions in innate immunity and inflammation
(Guo et al., 2015). In addition to their roles in infection, inflamma-
somes also play an important role in metabolic and neurological
diseases (Guo et al., 2015). The continued study of inflammasomes
will enhance our understanding of inflammatory responses to infec-
tion and of the role of inflammation in normal cell function and
disease.
HOW HAS IDENTIFYING CELLULAR TARGETS OF
PATHOGENS LED TO THE DEVELOPMENT OF
THERAPEUTIC AGENTS TO TREAT INFECTION?
There are two predominant approaches for combating infectious
diseases. One is to stimulate the immune system to prevent or re-
duce the impact of infection, for example, through vaccination. An-
other is to reduce or eliminate an existing infection with drugs that
kill the infectious agent and/or enhance the immune response.
Studying the cell biology of pathogenesis is contributing to both of
these therapeutic avenues.
An interesting example involves an emerging connection be-
tween autophagy and vaccine efficacy. The bacillus Calmette-
Guerin (BCG) vaccine, used to combat tuberculosis caused by the
intracellular pathogen Mycobacterium tuberculosis, consists of an
attenuated strain of the related bacterium Mycobacterium bovis.
BCG has a protective effect against meningitis and disseminated
tuberculosis in children but does not prevent primary infection with
M. tuberculosis or reactivation of pulmonary infection, which is the
main route of spread of the disease. Thus a more effective vaccine
is needed. Interestingly, augmenting autophagy with rapamycin
was found to enhance presentation of a BCG antigen by antigen-
presenting cells and enhance protection against M. tuberculosis
infection in animal model (Jagannath et al., 2009). A similar phe-
nomenon was observed for the yellow fever vaccine YF-17D, a live
attenuated virus that, in contrast with BCG, is almost always effec-
tive in protecting against infection with the yellow fever virus. It was
shown that YF-17D stimulated expression of the kinase GCN2,
which in turn stimulated dendritic cells to initiate autophagy and
enhanced antigen presentation to T-cells (Ravindran et al., 2014).
These findings suggest that stimulating autophagy may be a gen-
eral strategy for enhancing antigen presentation and vaccine
efficacy.
In cases in which vaccination is not possible or fails to confer
protection, antiviral, antibacterial, and antiparasitic drugs are com-
monly used to treat infections. These drugs generally target
pathogen molecules that are both essential for pathogen growth
and are distinct from host molecules, enhancing the selective tox-
icity of the drug for the infectious agent while minimizing side ef-
fects on the host. This raises the following question: Can host cell
components that are important for pathogenesis also be effective
drug targets for treating infectious diseases? The answer is yes,
and it is noteworthy that targeting host molecules appears to be
an emerging strategy for the development of drugs to treat
infections.
Targeting host molecules has advanced the furthest in develop-
ing treatments for viral infections. Prime examples are drugs that
target host cell receptor molecules and prevent viral entry. Maraviroc
is a Federal Drug Administration (FDA)-approved drug that is used
in combination therapy to treat HIV infection. It inhibits viral entry
into cells by binding to the chemokine- and HIV-receptor CCR5
(Wood and Armour, 2005). Other inhibitors of host proteins in-
volved in HIV infection are also in development (Arhel and Kirch-
hoff, 2010). Moreover, inhibitors of the cellular receptors for other
viruses have been identified. A small molecule that inhibits cellular
infection with Ebola virus, the causative agent of a dramatic hemor-
rhagic fever, works by binding to the endosomal protein NPC1
(Côté et al., 2011). In fact, the identification of this inhibitor revealed
that NPC1 is a crucial factor for Ebola virus infection. A more recent
study identified an engineered protein that inhibits infection with
the influenza virus, which causes flu, by binding to sialic acid, which
is used as a receptor for virus entry (Connaris et al., 2014). One in-
tranasal dose of this inhibitor protected mice from an otherwise le-
thal dose of the 2009 pandemic H1N1 virus, while also enabling
sufficient viral replication to potentially protect the animals from fu-
ture infection.
Antibacterial agents that target host cell molecules are also be-
ing explored. Such agents will be particularly useful in cases for
which there is no effective vaccine, and/or resistance to conven-
tional antibiotics is common, as with M. tuberculosis. A recent fruit-
ful approach was to screen through a library of bioactive small mol-
ecules known to target host proteins for those that restrict the
growth of M. tuberculosis (Stanley et al., 2014). This identified
compounds that affect several protein classes, including G pro-
tein–coupled receptors, ion channels, membrane transport pro-
teins, kinases, and anti-inflammatories. Through this and other
studies, a list can be compiled of FDA-approved drugs that target
host molecules and inhibit M. tuberculosis infection, including the
antidepressants fluoxetine (Prozac; Stanley et al., 2014) and nor-
triptyline (Sundaramurthy et al., 2013); the epidermal growth factor
receptor kinase inhibitor gefitinib (Stanley et al., 2014) and Abl ki-
nase inhibitor imatinib (Napier et al., 2011; Bruns et al., 2012); and
the antiseizure medication carbamazepine (Schiebler et al., 2015).
A common theme linking these drugs is that they induce autoph-
agy, again highlighting the potential utility of autophagy-stimulat-
ing drugs in the prevention and treatment of infections (Rubinsztein
et al., 2015).
Finally, targeting components of the host cell may also prove
fruitful for combating infection by intracellular parasites such as Plas-
modium falciparum and other Plasmodium species, which are the
causative agents of malaria. During infection of host hepatocytes,
Plasmodium suppresses the expression of the cell cycle regulator
and proapoptotic protein p53 and increases the expression of the
antiapoptotic protein Bcl-2, thus preventing host cell apoptosis
(Kaushansky et al., 2013). It was recently found that counteracting
the parasite’s anti-apoptotic program by treatment with the small
molecule p53 activator Nutlin-3 and/or the Bcl-2 inhibitors Obato-
clax or ABT-737, all of which are under study as anticancer therapeu-
tics, delayed or prevented onset of disease caused by P. falciparum
(Douglass et al., 2015). This reveals the potential therapeutic value
of drugs that target host cell death molecules for treating infectious
disease.
Thus it appears that developing drugs that target host compo-
nents is a viable strategy to combat infectious diseases, and this
may prove complementary to the traditional approach of develop-
ing antimicrobials that target pathogen proteins. Although potential
drawbacks of such a strategy include the risk of toxicity to the host,
potential benefits may include an increased flexibility in developing
combination therapies and a reduced capacity of the pathogens to
become resistant to drug treatment.
Volume 26  December 1, 2015 Cell biology of pathogenesis | 4299
CONCLUSIONS AND FUTURE DIRECTIONS
In writing this Perspective, I hope to encourage cell biologists to
study pathogens by collaborating with pathogenesis researchers or
incorporating work on infectious diseases into their own research
programs. Such investigations might focus on well-known patho-
gens or new and emerging infectious agents. The motivation may
be a desire to reveal new biological principles or to better understand
and treat important diseases. Regardless of the choice of pathogen
or source of motivation, future studies by cell biologists will uncover
new ways in which pathogens influence host cell pathways and
structures, and new cell biological mechanisms that operate under
normal circumstances and in various disease states. Future studies
will also contribute to the development of new vaccines and drugs
that target host cell proteins to prevent or treat infections. Therefore
basic and translational research at the interface between microbiol-
ogy, cell biology, and immunology will be an increasingly important
source of information and innovation relevant to biology in general
and infectious disease in particular.
ACKNOWLEDGMENTS
I thank Rebecca Lamason and Chris Patane for helpful comments on
the manuscript. Work in the Welch lab is funded by National Insti-
tutes of Health grants R01 GM059609 and R01 AI109044.
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